Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation–contraction coupling and reduces oxidative stress in adult rat cardiomyocytes

Timolati, Francesco; Ott, Daniel; Pentassuglia, Laura; Giraud, M; Perriard, Jean‐Claude; Suter, Thomas M.; Zuppinger, Christian

doi:10.1016/j.yjmcc.2006.08.002

Cited by 162 publications

(129 citation statements)

References 38 publications

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“…The mechanism of this type of cellular injury is likely multifactorial including the formation of reactive oxygen species, elevation of cytoplasmic Ca 2? concentration and activation of intracellular proteases as well as inhibition of the mTOR signaling pathway and the cardiac transcription factor GATA4 (Lim et al 2004;Pentassuglia et al 2009;Timolati et al 2006;Zhu et al 2009). We have used myofibrillar changes as a marker for cancer therapy-associated cardiotoxicity with different classes of drugs such as paclitaxel, anti-ErbB2 antibodies, MEK-inhibitors and small tyrosine kinase inhibitors for ErbB1/ErbB2 (Pentassuglia et al 2007(Pentassuglia et al , 2009Sawyer et al 2002).…”

Section: Discussionmentioning

confidence: 99%

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

et al. 2009

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In failing hearts cardiomyocytes undergo alterations in cytoskeleton structure, contractility and viability. It is not known presently, how stress-induced changes of myofibrils correlate with markers for cell death and contractile function in cardiomyocytes. Therefore, we have studied the progression of contractile dysfunction, myofibrillar damage and cell death in cultured adult cardiomyocytes exposed to the cancer therapy doxorubicin. We demonstrate, that long-term cultured adult cardiomyocytes, a wellestablished model for the study of myofibrillar structure and effects of growth factors, can also be used to assess contractility and calcium handling. Adult rat ventricular myocytes (ARVM) were isolated and cultured for a total of 14 days in serum containing medium. The organization of calcium-handling proteins and myofibrillar structure in freshly isolated and in long-term cultured adult cardiomyocytes was studied by immunofluorescence and electron microscopy. Excitation contraction-coupling was analyzed by fura 2 and video edge detection in electrically paced cardiomyocytes forming a monolayer, and cell death and viability was measured by TUNEL assay, LDH release, MTT assay, and Western blot for LC3. Adult cardiomyocytes treated with Doxo showed apoptosis and necrosis only at supraclinical concentrations. Treated cells displayed merely alterations in cytoskeleton organization and integrity concomitant with contractile dysfunction and up-regulation of autophagosome formation, but no change in total sarcomeric protein content. We propose, that myofibrillar damage contributes to contractile dysfunction prior to cell death in adult cardiomyocytes exposed to clinically relevant concentrations of anthracyclines.

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Section: Discussionmentioning

confidence: 99%

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

et al. 2009

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“…Neuregulin1 treatment 3 hours prior to doxorubicin attenuated doxorubicin-induced alterations of contractility in cardiomyocytes (Timolati et al, 2006). Neuregulin1 decreased calcium amplitude and fractional shortening in 1µM doxorubicin-treated cardiomyocytes while increased these indices in 10µM doxorubicin-treated cells.…”

Section: Neuregulin1-erbb Signaling Maintains Calcium Homeostasis In mentioning

confidence: 88%

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

Goukassian¹,

Morgan²,

Yan³

2012

Cardiotoxicity of Oncologic Treatments

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“…Taken together, these studies point to a role for neuregulin's in modulating mitochondria mediated apoptosis. The capacity of NRG1 to protect both adult and neonatal cardiomyocytes from doxorubicin induced toxicity has been studied with both in vitro and in vivo systems [10,13,29]. However, the mechanism by which this occurs has not been fully elucidated.…”

Section: Mitochondria Related Gene Expression Arraymentioning

confidence: 99%

“…Loss of function for any of these 3 genes creates an embryonic lethal phenotype with disrupted trabeculation in the ventricular muscle. In vitro evidence that neuregulin's and their receptors contribute to proper functioning of adult cardiomyocytes was demonstrated in several studies related to survival [9][10][11], proliferation [6], hypertrophy [12], myofibrillar organization [12,13] and, more recently, their role in sympathovagal control in the heart [14,15]. GGF2 was found to promote survival and hypertrophy of adult rat ventricular cardiomyocytes [6].…”

Section: Introductionmentioning

confidence: 99%

Glial Growth Factor 2 protects doxorubicin exposed cardiomyocytes through BAD/Bcl-2 pathway activation

Srinivas¹,

Cao²,

Zilinski³

et al. 2017

Cardiovasc Disord Med

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Neuregulin/erbB signalling is cardioprotective as seen in models of cardiotoxicity associated with the use of chemotherapeutics. Our studies reveal a function of Bcl-2 to protect cardiomyocytes concomitant with GGF2-induced increases in levels of phospho-BAD (pBAD) along with activation of PI3 kinase (PI3K) and MAP kinase (MAPK). We show that phosphorylation of BAD is dependent upon GGF2 mediated activation of PI3K. In addition, examination of mitochondrial gene expression shows several members of the Bcl-2 family are down-regulated by doxorubicin, while GGF2 is able to reverse this effect. While many in vitro model systems of doxorubicin cardiotoxicity have observed PI3K-dependent cytoprotective effects of neuregulin's, the present results demonstrate that GGF2 mediates cytoprotective actions in HL-1 cardiomyocytes through regulation of mitochondrial mediated apoptosis via the PI3K/Bcl-2 pathway.

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Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation–contraction coupling and reduces oxidative stress in adult rat cardiomyocytes

Cited by 162 publications

References 38 publications

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

Glial Growth Factor 2 protects doxorubicin exposed cardiomyocytes through BAD/Bcl-2 pathway activation

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